lnterleukin-15 (IL-15) is cytokine with pleiotropic effects on the ontogeny, homeostasis, and physiology of innate and adaptive immune cells. Our focus over the past decade of this award has been on the association of IL-15 and natural killer (NK) cell biology and pathophysiology. Our progress during this past funding cycle has occurred during a seemingly unprecedented period of advancement in our understanding of NK cell development, biology, and therapeutic application. Our own contributions have revolved around the role of IL-15 in NK cell development and homeostasis at both the cellular and molecular level, including some recent intriguing data that may define the lymph node as a site of human CD56 (bright) NK cell development. We have demonstrated that deregulation of IL-15 leads to a pro-inflammatory cytokine cascade that ultimately results in a high frequency of monoclonal acute lymphoblastic leukemia of the T/NK lineage, establishing IL-15 as a player in the ever-increasing association between inflammation and cancer. Importantly, epigenetic alterations in the genome appear to be central to this process, and we have devised an effective technique to identify novel genes that are clearly targeted and silenced in a non-random fashion in T/NK leukemia. In the next five years of study we will focus on three aims initiated at the time of our last competitive renewal application, each unified by the common theme of IL-15 in innate immunity. We will evaluate: (1) the stages of NK cell development, especially in the context of cytokine responsiveness; (2) the role of two transcription factors that are downstream targets of IL-15 and appear to be involved in NK cell differentiation; (3) the role of IL-15 deregulation in the genesis of experimentally induced T/NK cell acute lymphoblastic leukemia, as well as therapeutic approaches to cure the disorder. Collectively, the work outlined in this proposal should provide important information on how to better manipulate NK cells for anti-leukemia therapy, as well as new insights into the relationship between inflammation and cancer.